Depressive Disorder, Major
Conditions
Brief summary
The purpose of this study is to assess the efficacy of a single (first) dose of 3 fixed doses of intranasal esketamine {28 milligram (mg), 56 mg, and 84 mg} compared with psychoactive placebo (oral midazolam) in rapidly reducing the symptoms of major depressive disorder (MDD) including suicidal ideation in participants 12 to less than 18 years of age who are assessed to be at imminent risk for suicide.
Detailed description
This study will enroll participants with major depressive disorder (MDD) presenting with suicidal ideation who are assessed to be at imminent risk for suicide. The study will be conducted in 4 phases: a screening evaluation performed within 48 hours prior to Day 1 intranasal dose; a 25-day double-blind treatment phase (Days 1-25); an 8-week initial post-treatment phase (Days 25-81); and a subsequent phase to complete a full 6-month post-treatment follow-up (Days 81-200). Efficacy, safety, pharmacokinetic, biomarker, and pharmacogenomic evaluations will be performed in the study at defined schedule. The duration of the participant's participation will be approximately 29 weeks. If you or a loved one are having thoughts of suicide, please seek immediate medical help. Go to the emergency room or call the National Suicide Prevention Lifeline at 1-800-273-8255.
Interventions
DRUGIntranasal Placebo
Participants will receive placebo as intranasal dose to match intranasal esketamine.
DRUGMidazolam Placebo Solution
Participants will receive placebo as oral dose to match midazolam drug.
DRUGMidazolam
Participants will receive midazolam solution 0.125 mg/kg as oral dose to match placebo.
DRUGEsketamine
Participants will receive esketamine at a dose of 28 mg as intranasal solution.
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
9 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Participants must meet diagnostic and statistical manual of mental disorders (5th edition) {DSM-5} diagnostic criteria for major depressive disorder (MDD), without psychotic features, based upon clinical assessment and confirmed by the mini international neuropsychiatric interview for children and adolescents (MINI KID) * Participant must have a children's depression rating scale-revised (CDRS-R) total score of equal or more than (\>=) 58 predose on Day 1 * As part of standard of care treatment, participant must agree to be hospitalized voluntarily for a recommended period of 5 days after randomization (may be shorter or longer if clinically warranted in the investigator's opinion) * As part of the newly initiated or optimized standard of care treatment, participant must agree to take one of the prescribed non-investigational antidepressant medications (fluoxetine, escitalopram, sertraline; and 9-11 years old participants at US-sites only: fluoxetin \[preferred\], sertraline) at least during the double-blind treatment phase (Day 25) * As part of standard of care treatment, participant must agree to participate in a specific psychological intervention (individual cognitive behavioral therapy \[CBT\], interpersonal therapy, family therapy or psychodynamic psychotherapy) at least through the initial 8-week post-treatment follow-up period (Day 81)
Exclusion criteria
* Participants has a current DSM-5 diagnosis of bipolar (or related disorders), intellectual disability, autism spectrum disorder, conduct disorder, anorexia nervosa, oppositional defiant disorder, or obsessive compulsive disorder * Participants currently meets DSM-5 criteria for borderline personality disorder. Participants not meeting full DSM-5 criteria for borderline personality disorder but exhibiting recurrent suicidal gestures, threats, or self-mutilating behaviors should also be excluded * Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis * Participant meets the DSM-5 severity criteria for moderate or severe substance or alcohol use disorder (except for nicotine or caffeine) within the 6 months before screening. A history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder is exclusionary * Participant has a history of seizure disorder
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2) | Baseline (predose on Day 1) and 24 hours post first dose on Day 1 (i.e., Day 2) | The CDRS-R is a validated 17- item, clinician-rated instrument developed to assess depressive symptomatology in children. Scores were based on interviews with both the child and their caregiver. Of the 17-item, 3 items were non-verbal behavior (listless speech, hypoactivity, and depressed affect) rated on a 5-point scale from 1 (no depression) to 5 (severe depression) and 14 items were rated on a 7-point scale from 1 (no depression) to 7 (severe depression), where higher score indicated more severe depression. The CDRS-R total score was the sum of the 17-tems score and it ranged from 17 (normal) to 113 (severe depression). Higher score indicated more severe depression and worse outcome. |
Countries
Belgium, Brazil, Bulgaria, France, Hungary, Italy, Poland, Spain, United States
Participant flow
Recruitment details
A total of 147 participants were randomized and treated. One participant (randomized to arm Esketamine 84 mg+Placebo+standard of care \[SOC\]) was excluded from the efficacy analysis set, safety analysis set, and follow-up analysis set due to Good Clinical Practice (GCP) issue at the site.
Pre-assignment details
Adolescent participants with major depressive disorder (MDD) who were assessed to be at imminent risk for suicide were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo + Midazolam + SOC In the double blind (DB) phase, participants received 3 intranasal doses of placebo (matched to esketamine nasal spray) using 3 devces, each device at time points 0, 5 and 10 minutes (min) respectively. For each device, 1 spray was administered into each nostril (that is total of 2 sprays/device). An oral solution of midazolam 0.125 milligrams per kilogram (mg/kg) was administered immediately before the first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During the study, all participants were treated with Standard of care (SOC): antidepressant treatment (either fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated, or optimized on Day 1 or up to 7 days after first dose of study drug administration (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB treatment phase, participants entered post-treatment follow-up (FU) phase and received no study drug. | 63 |
| Esketamine 28 mg + Placebo + SOC In DB phase, participants received 1 intranasal dose of esketamine 28 mg nasal spray using a device, at 0 min, followed by 2 intranasal doses of placebo (matched to esketamine) using 2 devices, 1 at 5 min and another at 10 min, respectively. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug. | 29 |
| Esketamine 56 mg + Placebo + SOC In DB phase, participants received 2 intranasal doses of esketamine 56 mg nasal spray using 2 devices, 1 at 0 min and another at 5 min, followed by 1 intranasal dose of placebo (matched to esketamine) using 1 device at 10 min. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug. | 31 |
| Esketamine 84 mg + Placebo + SOC In DB phase, participants received 3 intranasal doses of esketamine 84 mg nasal spray using 3 devices, each device at 0, 5 and 10 min, respectively. For each device, 1 spray (esketamine 14 mg/placebo) was administered into each nostril (that is total of 2 sprays = esketamine 28 mg/placebo). Placebo oral solution (matched to midazolam 0.125 mg/kg) was administered immediately before first intranasal dose. Study drugs were taken 2 times per week for 4 weeks (on Days 1, 4, 8, 11, 15, 18, 22, and 25). During study, all participants received SOC: antidepressant treatment (fluoxetine or escitalopram or sertaline) based on clinical judgement, initiated or optimized on Day 1 or up to 7 days after first dose (on Day 1), if starting two medications simultaneously was not consistent with local clinical practice, and psychotherapy. After DB phase, participants entered post-treatment FU phase and received no study drug. | 23 |
| Total | 146 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Phase: Day 1 to Day 25 | Adverse Event | 1 | 0 | 0 | 0 |
| Double-Blind Phase: Day 1 to Day 25 | Lack of Efficacy | 2 | 0 | 1 | 0 |
| Double-Blind Phase: Day 1 to Day 25 | Other | 1 | 0 | 1 | 0 |
| Double-Blind Phase: Day 1 to Day 25 | Subject refused further study treatment | 0 | 0 | 0 | 1 |
| Double-Blind Phase: Day 1 to Day 25 | Withdrawal by parent/guardian | 0 | 0 | 0 | 1 |
| Post-treatment Follow-up: Days 26 to 200 | Adverse Event | 0 | 1 | 0 | 0 |
| Post-treatment Follow-up: Days 26 to 200 | Death | 1 | 0 | 0 | 0 |
| Post-treatment Follow-up: Days 26 to 200 | Lost to Follow-up | 2 | 1 | 0 | 2 |
| Post-treatment Follow-up: Days 26 to 200 | Other | 1 | 0 | 3 | 1 |
| Post-treatment Follow-up: Days 26 to 200 | Physician Decision | 2 | 0 | 2 | 0 |
| Post-treatment Follow-up: Days 26 to 200 | Requires treatment with electroconvulsive therapy, transcranial magnetic stimulation, ketamine | 1 | 0 | 0 | 0 |
| Post-treatment Follow-up: Days 26 to 200 | Withdrawal by parent/guardian | 1 | 0 | 1 | 0 |
| Post-treatment Follow-up: Days 26 to 200 | Withdrawal by Subject | 3 | 3 | 2 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo + Midazolam + SOC | Esketamine 28 mg + Placebo + SOC | Esketamine 56 mg + Placebo + SOC | Esketamine 84 mg + Placebo + SOC |
|---|---|---|---|---|---|
| Age, Continuous | 14.9 years STANDARD_DEVIATION 1.46 | 15.2 years STANDARD_DEVIATION 1.45 | 14.9 years STANDARD_DEVIATION 1.33 | 14.8 years STANDARD_DEVIATION 1.52 | 14.3 years STANDARD_DEVIATION 1.43 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 146 Participants | 63 Participants | 29 Participants | 31 Participants | 23 Participants |
| Age, Customized Adults (18-64 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65 to 84 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 16 Participants | 7 Participants | 8 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 104 Participants | 46 Participants | 19 Participants | 20 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 1 Participants | 3 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 6 Participants | 4 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 0 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 118 Participants | 53 Participants | 25 Participants | 23 Participants | 17 Participants |
| Sex: Female, Male Female | 114 Participants | 48 Participants | 24 Participants | 25 Participants | 17 Participants |
| Sex: Female, Male Male | 32 Participants | 15 Participants | 5 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 63 | 0 / 29 | 0 / 31 | 0 / 23 | 1 / 59 | 0 / 29 | 0 / 29 | 0 / 21 |
| other Total, other adverse events | 57 / 63 | 26 / 29 | 30 / 31 | 23 / 23 | 48 / 59 | 21 / 29 | 19 / 29 | 14 / 21 |
| serious Total, serious adverse events | 9 / 63 | 4 / 29 | 7 / 31 | 1 / 23 | 19 / 59 | 10 / 29 | 8 / 29 | 7 / 21 |
Outcome results
Primary
Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2)
The CDRS-R is a validated 17- item, clinician-rated instrument developed to assess depressive symptomatology in children. Scores were based on interviews with both the child and their caregiver. Of the 17-item, 3 items were non-verbal behavior (listless speech, hypoactivity, and depressed affect) rated on a 5-point scale from 1 (no depression) to 5 (severe depression) and 14 items were rated on a 7-point scale from 1 (no depression) to 7 (severe depression), where higher score indicated more severe depression. The CDRS-R total score was the sum of the 17-tems score and it ranged from 17 (normal) to 113 (severe depression). Higher score indicated more severe depression and worse outcome.
Time frame: Baseline (predose on Day 1) and 24 hours post first dose on Day 1 (i.e., Day 2)
Population: Full efficacy analysis set for DB phase included all randomized participants who received at least 1 dose of DB study medication during the DB phase and had both baseline \& post dose evaluation for CDRS-R total score. As pre-planned in study statistical analysis plan (SAP), data were planned to be collected and analyzed on pooled population who had received esketamine (56 mg/84 mg) in arms Esketamine 56 mg + Placebo + SOC and Esketamine 84 mg + Placebo + SOC respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo + Midazolam + SOC | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2) | -26.2 Units on a scale | Standard Deviation 16.72 |
| Esketamine 28 mg + Placebo + SOC | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2) | -29.6 Units on a scale | Standard Deviation 18.15 |
| Esketamine 56 mg + Placebo + SOC | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2) | -31.8 Units on a scale | Standard Deviation 12.92 |
| Esketamine 84 mg + Placebo + SOC | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2) | -30.3 Units on a scale | Standard Deviation 17.48 |
| Pooled Esketamine 56 mg + Esketamine 84 mg | Change From Baseline in Children's Depression Rating Scale-Revised (CDRS-R) Total Score at 24 Hours Post First Dose (Day 2) | -31.2 Units on a scale | Standard Deviation 14.9 |
Comparison: A pooled (54 mg and 84 mg) sequential multiple testing procedure was implemented to control type I error by comparing pooled data against midazolam + placebo matched to esketamine nasal spray.p-value: =0.03795% CI: [-11.19, -0.35]ANCOVA
Comparison: Individual esketamine dose (84 mg versus medazolam + esketamine matched placebo) independent testing was planned to be performed after pooled (56 mg + 84 mg) analysis.p-value: =0.12395% CI: [-12.91, 1.55]ANCOVA
Comparison: Individual esketamine dose (56 mg versus medazolam + esketamine matched placebo) independent testing was planned to be performed after pooled (56 mg + 84 mg) analysis.p-value: =0.07295% CI: [-12.25, 0.53]ANCOVA
95% CI: [-9.08, 4.19]